Periodontal disease, characterized by dysregulated immune response to oral microbiome, is one of the most prevalent chronic inflammatory diseases affecting humans. In the United States, periodontal disease affects approximately 46% of the adults aged 30 years and above, with 9% having severe periodontitis. The impact of periodontal disease in terms of social, psychological and economic burden on individuals, communities and health services is enormous. Despite these concerns, the molecular mechanisms regulating inflammatory-mediated tissue destruction in periodontal disease remains unclear, creating a critical knowledge gap in developing targeted interventions for periodontal disease. This K99/R00 application is aimed at advancing the fundamental knowledge of immunopathological mechanisms contributing to inflammatory-mediated tissue destruction in periodontal disease. Recently, the candidate has identified novel mutations in the interferon regulatory factor 8 gene (IRF8) that increase susceptibility to periodontal disease in humans and mice. The goals of the proposed research are to delineate the molecular mechanisms by which IRF8 functions to maintain a healthy periodontium and how specific mutations in IRF8 disrupt periodontal homeostasis, which will further contribute to better understanding of other inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and multiple sclerosis that have known risk alleles in IRF8. The proposed multi-disciplinary project capitalizes on novel IRF8 mutant animal models and human subjects available at the NIH. The applicant is a postdoctoral research fellow at the NIH and is highly qualified to lead this research program based on his research training in bone remodeling and periodontal disease, coupled with his clinical expertise as a board certified periodontist. The candidate's long-term career goal is to lead a productive research program that provides significant insights into periodontal disease pathogenesis, and translate those insights into tangible clinical applications such as diagnostic and prognostic screening tests, prevention strategies, and therapeutic interventions. The proposed project is an ideal starting point for the candidate to transition into an independent research career because it provides a framework for developing further skills necessary to accomplish the long-term goal. The proposed career development plan incorporates didactic coursework, laboratory training, and a structured mentorship plan to facilitate accomplishment of short-term goals, including development of a skill set for periodontal disease research, establishment of an independent research project, providing a pathway for obtaining a tenure-track faculty position at a top-tier dental school, and providing future opportunities to build on the proposed research. The applicant's institutional environment offers exceptional opportunities for research and career development training and is committed towards candidate's successful transition into an independent investigator.